JAK3 deregulation by activating mutations confers invasive growth advantage in extranodal nasal-type natural killer cell lymphoma

Abstract

Extranodal, nasal-type natural killer (NK)/T-cell lymphoma (NKCL) is an aggressive malignancy with poor prognosis in which, usually, signal transducer and activator of transcription 3 (STAT3) is constitutively activated and oncogenic. Here, we demonstrate that STAT3 activation mostly results from constitutive Janus kinase (JAK)3 phosphorylation on tyrosine 980, as observed in three of the four tested NKCL cell lines and in 20 of the 23 NKCL tumor samples under study. In one of the cell lines and in 4 of 19 (21%) NKCL primary tumor samples, constitutive JAK3 activation was related to an acquired mutation (A573V or V722I) in the JAK3 pseudokinase domain. We then show that constitutive activation of the JAK3/STAT3 pathway has a major role in NKCL cell growth and survival and in the invasive phenotype. Indeed, NKCL cell growth was slowed down in vitro by targeting JAK3 with chemical inhibitors or small-interfering RNAs. In a human NKCL xenograft mouse model, tumor growth was significantly delayed by the JAK3 inhibitor CP-690550. Altogether, the constitutive activation of JAK3, which can result from JAK3-activating mutations, is a frequent feature of NKCL that deserves to be tested as a therapeutic target.

EZH2 phosphorylation by JAK3 mediates a switch to noncanonical function in natural killer/T-cell lymphoma

“…We found a significant correlation between JAK/STAT activation and increase expression of canonical PRC2 genes in our Asian NKTL patients. Our results are consistent with reports showing that most NKTL expressed phosphorylated JAK3 regardless of their JAK3 mutation status, 9 and several gene sets related to the PRC2 complex were enriched among these upregulated genes. 21 Conversely, phosphorylated EZH2 associates with Pol II at the promoters of noncanonical target genes and "actively" regulate the expression of these genes.…”

“…Strikingly, 35.4% cases of NKTL harbor such JAK3 activating mutations, which confer the growth advantage in NKTL. 8,9 In this study, we exploited a possible functional interaction between EZH2 and JAK3 in NKTL where both molecules are highly oncogenic to induce similar proliferative phenotypes. We found that JAK3 induces the phosphorylation of EZH2 to establish the oncogenic function of EZH2 independent of its catalytic activity.…”

Activating mutations of STAT5B and STAT3 in lymphomas derived from γδ-T or NK cells

“…Two recent studies reported the presence of JAK3 A572V, A573V or V722I mutations in NKTCLs 6,7 . However, neither WTS nor hotspot sequencing of 40 NKTCL cases revealed these SNVs, consistent with a recent report 8 .…”

Aspects moléculaires des lymphomes T périphériques (2)

“…Les mutations de JAK3 (Janus kinase 3) sont en effet observées chez 20 à 30 % des patients [31,32]. Les mutations de STAT3 (signal transducer and activator of transcription 3), bien que fréquemment retrouvées dans les lymphoproliférations chroniques NK et les leucémies à grands lymphocytes à grains [33,34], semblent plus rares dans les lymphomes NK/T où elles ne sont observées que chez 6 à 10 % des patients [35,36].…”

“…Toutes les mutations décrites de STAT3 ou STAT5B affectent le domaine SH2 de la protéine ; elles entraînent une phosphorylation constitutive de la protéine et favorisent la croissance des lignées cellulaires infectées. De façon intéressante, les inhibiteurs de JAK1/JAK2 (comme le ruxolitinib) entraînent, in vitro, une diminution de la prolifération des lignées mutées pour JAK3 ou STAT3/STAT5B [31,32,35] et, in vivo, une régression de la croissance tumorale dans des modèles de xénogreffes [31,32] L'autre protéine importante dans le processus de pathogenèse est HBZ (HTLV-1 bZIP factor). Celle-ci est codée par le brin antisens du provirus HTLV-1 à partir de la région 3'LTR.…”